Summary

The incorporation of novel targeted therapies to radiation therapy is of particular interest
in head and neck cancer and may improve efficacy without significantly increasing toxicity.
The investigators hypothesize that the addition of a second EGFR-targeted agent that
inhibits EGFR at the intracellular level will improve the antitumor effect of standard
radiation and cetuximab. The goal of this study is to evaluate the safety, efficacy, and the
biologic effects in patients with locally advanced SCCHN of an antisense gene targeting the
EGFR in combination with standard therapy with radiation and cetuximab.

Study Design

EGFR AS will be administered by direct intratumoral injection using direct visualization, endoscopy, or imaging-guidance (ultrasound) as clinically determined. Patients will receive a total of up to 4 weekly intratumoral injections of EGFR antisense (or less if there is no identifiable tumor) starting 2 weeks prior to radiation. Patients will receive standard radiation 70 Gy/200 cGy/daily, 5 days/week, with concurrent cetuximab 250 mg/m2, after a loading dose of 400 mg/m2 2 weeks prior to starting radiation.

egfr antisense dna

EGFR AS will be administered by direct intratumoral injection using direct visualization, endoscopy, or imaging-guidance (ultrasound) as clinically determined. Patients will receive a total of up to 4 weekly intratumoral injections of EGFR antisense (or less if there is no identifiable tumor) starting 2 weeks prior to radiation. Patients will receive standard radiation 70 Gy/200 cGy/daily, 5 days/week, with concurrent cetuximab 250 mg/m2, after a loading dose of 400 mg/m2 2 weeks prior to starting radiation.

Primary Outcomes

Measure

Toxicity rate

time frame:
1 year

Locoregional Progression-free survival

time frame:
1 year

Secondary Outcomes

Measure

Tumor response

time frame:
5 years

Progression-free survival

time frame:
10 years

Overall Survival

time frame:
5 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria:
- First stage Patients with AJCC 7th edition stage IVA-IVC or recurrent or metastatic
head and neck cancer will be eligible. Patients with M1 disease must have
asymptomatic or low volume distant metastasis and require palliation for local and
regional disease.
- Second stage (phase II part) Patients with AJCC 7th edition stage III-IVB (T1-T4,
N1-3M0) head and neck cancer, except WHO type II and III nasopharyngeal cancer,
including unknown primary tumors.
- Histologically or cytologically confirmed diagnosis of squamous cell carcinoma or
variants or poorly differentiated carcinoma.
- Unidimensionally measurable disease (RECIST criteria).
- ECOG performance status of 0-2
- In the second stage of the study, therapy will be administered with a curative intent
and patients should not have recurrent disease or distant metastasis.
- Primary tumor and/or lymphadenopathy should be technically suitable for intratumoral
injections. The Otolaryngologist specialist on the head and neck team will determine
this feasibility.
- Participating patients should agree to undergo a tumor biopsy at baseline as well as
approximately 2 weeks later as specified in study schema.
- Prior treatment
- First stage: any prior treatment, except prior therapy, which specifically and
directly targets the EGFR pathway, administered within the last 6 months. No prior
radiation therapy to the head and neck.
- Second stage: no prior chemotherapy, biologic/molecular targeted therapy (including
any prior therapy which specifically and directly targets the EGFR pathway), or
radiotherapy for head and neck cancer.
- Prior surgical therapy will consist only of incisional or excisional biopsy,
including tonsillectomy, and organ sparing procedures, including neck dissection. Any
non-biopsy surgical procedure for head and neck cancer must have taken place at least
one month before initiating protocol treatment, at the treating physician's
discretion.
- Patients must have organ and marrow function as defined below:
Absolute neutrophil count above/equal to 1,000/µL Platelets above/equal to 75,000/µL
Hemoglobin above/ equal to 10 g/dL Total bilirubin <2 x upper normal institutional limits
Creatinine clearance > 20 mL/min
- Age 18 years or older
- Because radiation therapy is known to be teratogenic and EFGR inhibitors may have
teratogenic potential, women of childbearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control) prior to study
entry and for the duration of study participation, and for 3 months after completing
study treatment. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
- Informed consent must be obtained from all patients prior to beginning therapy.
Patients should have the ability to understand and the willingness to sign a written
informed consent document.
Exclusion Criteria:
- Severe renal insufficiency (creatinine clearance < 20 mL/min)
- Treatment with anticoagulants, except when used to maintain the patency of a central
venous line, or INR >1.5, or PTT ratio >1.5.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements. Significant history of uncontrolled cardiac disease; i.e.,
uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure.
- Patients may not be receiving any other investigational agents.
- No history of prior malignancy, with the exception of curatively treated squamous
cell or basal carcinoma of the skin or in situ cervical cancer, DCIS or LCIS of the
breast, localized early stage prostate cancer, or malignancy that has been treated
with a curative intent with a 3-year disease-free survival.
- Pregnant women are excluded from this study because cetuximab, EGFR AS, and radiation
have the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with cetuximab and EGFR AS, breastfeeding should be
discontinued if the mother is treated with cetuximab. The effects of cetuximab and
EGFR AS on the developing human fetus at the recommended therapeutic dose are
unknown. For this reason women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while in this study, she should inform her treating physician
immediately.
- HIV-positive patients receiving combination anti-retroviral therapy are excluded from
the study because of possible drug interactions with cetuximab. Appropriate studies
will be undertaken in patients receiving combination anti-retroviral therapy when
indicated. HIV status of the patient will be obtained from the patient's history via
discussion with the investigator. HIV testing is not required.
- Prior severe infusion reaction to a monoclonal antibody.
- Patients who are not informed of and are not willing to comply with the
investigational nature of the study and have not signed a written informed consent in
accordance with institutional and good clinical practice guidelines.
- Phase 2 ONLY (second stage) - Subjects M1 disease will be excluded.

Additional Information

Official title

Safety and Efficacy of Radiation and Cetuximab Plus Intratumoral EGFR Antisense DNA in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma

Principal investigator

Ahmad Wehbe, MD

Description

The Epidermal Growth Factor Receptor (EGFR) is highly expressed in SCCHN and its
overexpression is associated with poor patient outcome. EGFR is a promising target of
anticancer therapy. The investigators have developed EGFR antisense DNA as a safe and
potentially efficacious treatment for SCCHN as shown in a previous phase I study conducted
at the University of Pittsburgh. Cetuximab (Erbitux or C225) is a chimerized EGFR monoclonal
antibody that has produced positive results in a phase III trial in SCCHN when added to
radiation therapy and was approved by the FDA for the treatment of locally advanced SCCHN.
Radiation plus cetuximab is considered a standard treatment, especially for patients who are
not good candidates for chemotherapy. In the current study, the investigators plan to
evaluate the addition of intratumoral EGFR antisense DNA (EGFR AS) to standard radiation
with concurrent cetuximab in patients.
Objectives
- To evaluate the safety of the combination of intratumoral EGFS AS DNA with standard
cetuximab and radiation.
- To evaluate the locoregional progression-free survival in selected patients with
locally advanced SCCHN treated with intratumoral EGFR AS DNA combined with standard
radiation plus cetuximab.
- To evaluate other efficacy parameters, including the objective response rate, distant
control and overall progression-free survival, and overall survival.
- To determine the effect of EGFR antisense therapy on EGFR-related biomarkers. The
investigators will use reverse phase protein microarrays (RPPA) and immunohistochemical
(IHC) analysis of tissue microarrays (TMA) on baseline and post-treatment tumor tissue
to determine the expression level and modulation of a panel of EGFR and EGFR-pathway
related biomarkers, including (but not necessarily limited to) EGFR, pEGFR, Src, pMAPK,
STAT3, pSTAT3, pSTAT5, pSTAT1, pAKT, p38, p21, p27, PARP, E-cadherin, p-ErbB3, and
Ki67.
- To examine the transfection of the EGFR antisense gene therapy in vivo.
Subject population
The investigators will enroll patients with SCCHN who are suitable for intratumoral
injections of EGFR antisense.
Treatment plan
EGFR AS will be administered by direct intratumoral injection using direct visualization,
endoscopy, or imaging-guidance (ultrasound) as clinically determined (see protocol).
Patients will receive a total of up to 4 weekly intratumoral injections of EGFR antisense
(or less if there is no identifiable tumor) starting 2 weeks prior to radiation (study
schema in protocol). Patients will receive standard radiation 70 Gy/200 cGy/daily, 5
days/week, with concurrent cetuximab 250 mg/m2, after a loading dose of 400 mg/m2 2 weeks
prior to starting radiation.
Statistical Design and Sample Size
The study will be conducted in two-stages. In the first stage, 11 patients with stage IVA-C
or recurrent disease will be evaluated for safety. If the regimen is deemed safe, a total of
31 patients with stage III or IVA-B, previously untreated SCCHN will be enrolled in the
second stage of the study.

Trial information was received from ClinicalTrials.gov and was last updated in December 2015.

Information provided to ClinicalTrials.gov by The University of Texas Health Science Center at San Antonio.

Call for more information

Request more information

Trial Details

Related Tags

A synthetic sequence of DNA constructed in the antisense orientation to a sequence of DNA in epidermal growth factor receptor (EGFR), a member of the erbB gene family. EGFR antisense DNA suppresses the expression of EGFR by tumor cells, thereby inhibiting